The application of numerous, generator-produced, radioactive isotopes in patients has significantly advanced the fields of medical imaging, diagnosis and even therapy. Such patient-grade, generator-produced, radioisotopes are often called "daughter" radioisotopes because they are formed by the radioactive decay of different nuclides, called "parent" radioisotopes having considerably longer half-lives. Daughter radioisotopes are harnessed in a process called "elution," whereby a sterile "eluent," such as a sodium chloride solution, passes through a radioisotope generator column, upon which a decaying parent radioisotope is adsorbed, and exits as an "eluate" containing the daughter radioisotope.
Certain daughter radioisotopes, such as technetium-99 m, are primarily gamma photon emitters, making them ideal for imaging applications. Conventionally, these types of radioisotopes are prepared for medical use in a single elution step; that is, by forcing the eluent through the generator and capturing the resultant eluate.
Other radioisotopes decay with beta-charged emissions that are more readily absorbed by the patient, thus making them more suitable for therapy applications, such as radiolabeling, or radioimmunotherapy, and even pain therapy. Rhenium-188, which is eluted from a Tungsten-188 parent, is one such type of radioisotope whose beta emissions are entirely absorbed by the patient's body and has a relatively short-half life of 17.0 hours. These characteristics make Re-188 particularly useful for the treatment of tumors, i.e. radiolabeling, and other diseases and disorders. However, to be effective for such applications, Re-188 eluate, and other similar radioisotopes solutions, must be highly concentrated. Thus, they require additional purification and concentration steps.
In order to increase the activity concentration of the eluate produced by a typical generator, such as an alumina-based, tungsten-188/rhenium-188 (W-188/Re-188) generator, and to obtain treatment-quality Re-188, the eluate must be chemically "filtered" to remove traces of the parent radioisotope, alumina and chloride anions from the solution. The purified Re-188 isotope is then trapped, or concentrated, in an appropriate "radioisotope trap," such as an ion exchange column, and is then finally re-eluted into a container with a desired volume of fresh eluent.
One such system and process, developed by the Oak Ridge National Laboratory (ORNL), is shown in FIG. 1. In particular, the system 1 calls for the use of a constant flow-rate pump 2, namely, a peristaltic pump, to drive a desired volume of saline solution eluent stored in a container or sack 4, at a desired rate, through a series of single-use columns connected by tubing. The eluent is pumped through a radioisotope generator 6 and a filter 8 and the resultant eluate is forced through a series of single-use ion exchange columns 10 and 12. The first column 10 shown is a silver halide precipitation column ("Maxi Clean IC-Ag" column, Alitech, Inc., Deerfield, Ill.) that traps therein all of the chloride anions and permits the passage of any non-halide ions in the solution. An anion exchange column 12 (Accell Plus QMA.RTM. anion column, Waters, Inc., Milford, Mass.) referred to hereinafter as a radioisotope trap, then traps the perrhenate anions (the daughter radioisotope) therewithin, thus permitting the resultant eluate, which should contain only minimal radioactivity, to pass as a waste solution into a waste collection container 14 for disposal. Once the required volume of solution has been eluted, the operator disables the pump and manually adjusts each of the three-way valves 16, 18 and 20 to bypass the generator 6 and impurity traps 10 and 12 and to redirect the output from the waste container 14, to create a direct fluid path from the pump 2 to a collection vial 22. Then, in the second step, the operator reactivates the pump 2 to drive a small, predetermined, volume of fresh eluent from the supply 4 through tubing 17 and through the radioisotope trap 12, in order to elute, or more precisely, re-elute, the daughter radioisotope adsorbed on the column in the trap 12, into the sterile collection vial 22 as a sodium perrhenate solution.
While the ORNL system sets forth the basic chemistry, components and a method for the concentration and elution of discreet quantities sodium perrhenate, the system and method have several drawbacks. One problem is that the method relies on relatively significant operator intervention prior to, during, and after each elution. In particular, after setting up the system, the operator needs to set the flow rate of the pump, precisely track the on-time of the pump for the first elution, disable the pump, adjust the valves 16 and 18 to redirect the eluent for the second elution through the tube 17 to the radioactive trap 12, restart the pump for precisely long enough for the eluent to pass through tube 17, valve 18, radioisotope trap 12 (where, upon exiting, it becomes an eluate), and finally to valve 20. Just before this eluate reaches valve 20, valve 20 must be adjusted to redirect flow away from the waste container 14 and to the collection vial 22. This complex procedure is one method for maximizing the radioactive concentration in the collection vial. Alternatively, the operator can flush the system with air between elutions to purge the tubing of residual liquid that would otherwise dilute the radioactive eluate from the second elution. The air flush technique has the second advantage of reducing residual activity within the columns and tubing.
All of these steps tends to 1) be time-consuming and inefficient, especially for labs that engage in multiple, continuous elutions; 2) increase the potential for human error, which can be dangerous, wasteful or both; and 3) unduly expose the operator or operators to radiation.
It is understood that above-described system could be fully electronically controlled so that the electric pump would be automatically activated for the appropriate period of time, the three-way valves would then automatically be adjusted to their second stage positions, and the pump then reactivated for the final elution step. Nonetheless, such a system would add considerable complexity and cost to the conventional system, with the addition of a processor and electronic timer scheme. Further, such an automated system would not adequately address all of the aforementioned problems. Thus, it would desirable to have an inexpensive, simple, mechanical elution/concentration system that automatically produces concentrated radioisotopes and air purges the system, thus significantly reducing reliance on human intervention.
Further, using a constant, flow rate, electric pump to drive the solution through the system has drawbacks. Such pumps are relatively expensive, are ill-suited for pumping the air needed to purge the system after an elution, and run the risk of creating a dangerous over-pressure condition in the, albeit relatively rare, event of a blockage in the fluid line. Additionally, the requirement of an electric pump adds to system complexity and cost when the need to design for the different voltage supplies of various foreign countries is considered. Thus, it would be desirable to eliminate the need for a constant, flow rate, pump and, even more broadly, the need for electrical power, to both reduce system cost and to enable the production of a single design for the worldwide market.
A third drawback of the ORNL system is that it provides for separate, single use, concentration columns that must be properly connected and shielded by the operator for each fresh elution procedure. Further, the eluate waste created by the first stage elution must be properly disposed of. The set up and handling of these discrete components requires training, is inefficient, increases the risk of operator exposure, and creates the additional problem of the safe disposal of the spent, radioactive exchange columns and fluid waste. Thus, it would be desirable to have a system that minimizes component handling during both the set up and disposal procedures.
Another issue not fully addressed by preexisting systems relates to the inefficiency of the elution of generators. As a generator ages, its radioactive yield decreases due to its decay. While the elution of a fresh generator may yield a substantial quantity of the daughter isotope, a subsequent elution of that same generator may not yield enough end product for the procedure to be worthwhile. However, since each generator is relatively costly, it would be desirable to have a system that could easily and efficiently elute more than one aged generator in series, thereby producing, with a single elution, a useful quantity of the daughter radioisotope. This would effectively extend the useful life of generators that are located together and could decrease the medicine's cost per treatment.
In sum, a need therefore exists for a system and method that automatically concentrates and elutes radioisotope solutions, that automatically prepares the system for subsequent elution procedures, that does not rely on a costly and complex, processor-controlled pump arrangement, and that, at the same time, tends to minimize operator intervention and handling of the components and waste by-products.